MXPA06005482A

MXPA06005482A - PROCESSES FOR THE PREPARATION OF PYRAZOLO[1,5-a.

Info

Publication number: MXPA06005482A
Application number: MXPA06005482A
Authority: MX
Inventors: Kenneth C Mcnulty
Original assignee: Bristol Myers Squibb Pharma Co
Priority date: 2003-11-25
Filing date: 2004-11-19
Publication date: 2006-08-11
Also published as: US20070161790A1; WO2005051954A2; NO20062943L; TW200529827A; BRPI0416821A; CA2546652A1; WO2005051954A3; EP1706408A2; RU2006121075A; US7442792B2; JP2007512360A; US20050143380A1; AU2004293435A1; US7208596B2; AR046851A1; IL175753A0; PE20051045A1; KR20060116208A

Abstract

The present invention provides novel processes and intermediates for preparing corticotropin releasing factor (CRF) receptor antagonists having the structure below which are useful in treating CRF-related disorders such as anxiety and depression.

Description

CRFi leads to anxiolytic and antidepressant effects in rodents. Evidence from the animal model also shows that CRFi antagonists can help relieve withdrawal symptoms, stress-induced attacks, and certain inflammations. A role of CRF has been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, and lateral sclerosis, since they are related to the dysfunction of CRF neurons in the nervous system. central. Eating disorders, such as anorexia nervosa, have also been linked with elevated levels of CRF. Although widely dispersed throughout the central nervous system, CRF receptors are also found in peripheral systems that include the tissues of the glandular, vascular, gastrointestinal, and immune systems. In this way, CRF antagonists are believed to have potential in the treatment of various other disorders outside the central nervous system. Some disorders related to CRF of peripheral systems include, for example, hypertension, tachycardia, congestive heart failure, stroke, irritable bowel syndrome, postoperative ileus and colon hypersensitivity. Studies have indicated that CRFi antagonists may also be useful as stimulators of hair growth.

Pirazolo [1,5-a] -1,3,5-triazine derivatives have been identified as potent CRFi antagonists and are currently being studied as therapeutic agents for the treatment of various disorders related to CRF, including many of those aforementioned. Various CRFi antagonists of pyrazolotriazine have been reported in, for example, the patents of E.U.A. Nos. 6,124,289; 6,191,131; 6,313,124; 6,060,478; 6,136,809; and 6,358,950, as well as WO 02/72202 and WO 98/08847. The preparation of 3,5-triazine compounds typically involves a multi-step process that includes two-ring forming reactions to produce the bicyclic core. The syntheses of various pyrazolo [1, 5-a] -1, 3, 5-triazine compounds are reported in the above references as well as in WO 01/23388; US patents Nos. 4,824,834, 3,910,907, 5,137,887, 4,892,576, and 5,484,760; EP 594149; He et al., J. Med. Chem. 2000, 43, 449; Senga, et al. J. Med. Chem. 1982, 25, 243; Bruni, et al., J. Heterocycl. Chem., 1995, 32, 291; Kobe, et al., J. Het Chem., 1974, 991; Kobe, et al., J. Het. Chem., 1974, 199; Novinson, et al., J. Het. Chem., 1974, 691; and Albert, et. Al. J. Het. Chem., 1973, 885. Ring formation and other reactions are reported in Beyer, et al., 1960, 93, 2209 and Cusmano, et al., Gazz. Chi. Ital., 1952, 82, 373. Various active compounds of pyrazolo 3,5-triazine include a multi-substituted aryl or heteroaryl group, attached to the 8-position of the bicyclic core. The introduction of the substituent at 8 often involves the use of an aryl or heteroaryl acetonitrile derivative. Methods for the preparation of aryl or heteroaryl acetonitrile derivatives from the corresponding halomethyl and cyanide compound are reported in JP 2001302658; CN 1088574; and Nishida, et al., Technol. Rep. Yamaguchi Univ., 1988, 4 (2), 145. Other references that report reactions that can be used in the preparation of aryl or heteroaryl acetonitrile derivatives include, for example, Nagel, et al., J. Org. Chem., 1977, 42, 3626 and Stogryn, 1972, 37, 673 (metallation with n-BuLi of aryl bromides and condensation with DMF to form aldehydes); Li, et al., Tetrahedron Lett. 2001,1175 (reduction with sodium borohydride of benzyl aldehydes to benzyl alcohols); J. Org. Chem., 1970, 35, 3195, J.

Org. Chem., 1971, 36, 3044, Tetrahedron 1971, 27, 5979 (chlorination of benzyl alcohol with benzyl chloride and a base); J. Am. Chem. Soc., 1951, 73, 2239, J. Am. Chem. Soc., 1953, 2053 (conversion of benzyl chloride to the cyanide derivative); and Repic, Principles of Process Research and Chemical Development in the Pharmaceutical Industry, Wiley, 1998, p. 38. In view of the importance of 3,5-triazine derivatives in the treatment of disorders related to CRF such as anxiety and depression, improved methods for their synthesis are needed. Such improvements may include, for example, enhanced enantiomeric and / or diastereomeric selectivity in individual reaction steps, enhanced chemical purity, increasing yields, use of lower cost starting materials, use of less toxic starting materials, decreased energy consumption ( for example, avoid reactions at very high or very low temperatures or pressures), reduction in the number of synthetic stages, and improvement in scaling conditions. The processes and intermediaries discussed here help to meet these and other needs. Brief Description of the Invention The present invention provides, inter alia, processes and intermediates for preparing pyrazolo [1, 5-a] -1, 3, 5-triazines of Formula I below which are CRF receptor antagonists useful for treating disorders related to CRF including anxiety and depression. The present invention further provides processes and intermediates for preparing aryl and heteroaryl acetonitrile compounds useful as intermediates for preparing pyrazolo [1, 5-a] -1, 3, 5-triazines of Formula I. Detailed Description of the Invention The present invention provides , inter alia, processes for preparing pyrazolo [1,5-a] -1,3,5-triazines of Formula I: wherein: Ar is phenyl or pyridyl substituted with 0 to 5 R 3; each R1 and R2 is, independently, H, (C? -C8) alkyl, or alkoxyalkyl (Ci-Ce); each R3 is, independently, H, halo, CN, nitro, alkyl (C? -C), alkoxy (C? -C4), haloalkyl (C? -C4), or haloalkoxy (C1-C4); and each RA and RB is independently (C1-C4) alkyl. In some modalities, either or both and RB are methyl. In further embodiments, Ar can be 2-methyl-4-methoxyfile, 2-chloro-5-fluoro-4-methoxyfryl, or 2-methyl-6-methoxypyrid-3-yl. Still in further embodiments, both R1 and R2 can be methoxyethyl, or R1 is H and R2 is pent-3-yl, or R1 is H and R2 is but-2-yl. According to the present invention the processes for preparing compounds of Formula I may comprise the steps of: (a) contacting a compound of Formula III: with P0X3 in the presence of an amine, preferably a sterically overloaded amine, selected from diisopropylethylamine, diethylphenylamine, diisopropylaniline, diethylaniline, diisopropylisobutylamine, tribencylamine, triphenylamine, diethylisopropylamine wherein X is halo, for a time and under conditions sufficient to provide a compound of the Formula II: Y; (b) contacting the compound of Formula II with NHR1R2 for a time and under conditions sufficient to provide the compounds of Formula I. The reaction of step (a) involves the replacement of a hydroxyl portion in the intermediate of Formula III with a derivative of the halogen portion of the POX3 reagent. The example of POX3 reagents include POF3, P0C13, POBr3, and the like. In some modalities, X is Cl. The amine of step (a) can serve as a catalyst for halogenation. Suitable amines are typically volume tertiary amines selected from, for example, diisopropylethylamine, diethylphenylamine, diisopropylaniline, diethylaniline, diisopropylisobutylamine, tribencylamine, triphenylamine, tricyclohexylamine, diethylisopropylamine. In some embodiments, diisopropylethylamine is used as the amine catalyst. The molar ratio of the amine catalyst for POX3 can be about 1: 1. In some modalities, by contacting the stage (a) it is carried out in the presence of an ammonium salt which can act as a phase transfer agent.

Any ammonium salt is adequate. Some examples of ammonium salts include benzyltriethylammonium chloride, benzyltributylammonium chloride, Adogens®, (methyltrialkyl chloride) (C8-C? O) ammonium). In some embodiments, the ammonium salt is benzyltriethylammonium chloride. The ammonium salt can be provided in a catalytic amount. Examples of amount of ammonium salt are at least 1 eq (against the compound of Formula III). By contacting step (a) can be carried out in any solvent that is not reactive under the reaction conditions. Preferred solvents for this transformation are methyl t-butyl ester, acetonitrile, isopropylacetate, toluene and 1-chlorobutane. Suitable reaction conditions may include temperatures and ambient pressure of about 50 to about 110 ° C, preferably about 50 to about 70 ° C.

The reaction of step (b) involves the replacement of a portion of halogen in intermediates of Formula II with an amine amount. Any primary and secondary amine is suitable, such as an amine having the formula NHR1R2. The amine may be provided in an excess amount relative to the compound of Formula II (or Formula III). Some amines of the Formula NHR1R2 may include, for example, Any suitable solvent can be used to carry out the reaction of step (b). According to some embodiments, the reaction of step (b) can be carried out in an inorganic solvent. Some examples of organic solvents include methyl t-butyl ester, acetonitrile, isopropyl acetate, toluene, and 1-chlorobutane. In some embodiments, the organic solvent comprises either or both acetonitrile and methyl t-butyl ester, such as a mixture of acetonitrile and methyl t-butyl ester. An example of acetonitrile: methyl t-butyl ester ratio v / v can be about 1: 4. The reaction of step (b) can be carried out under ambient temperature and pressure. An example of temperature can be from about 0 to about 50 ° C.

In some embodiments, the intermediary of Formula II can be reacted in situ and not isolated prior to carrying out the reaction of step (b). The present invention further provides processes for a first ring closure wherein a compound of Formula III is prepared by (c) upon contacting a compound of Formula IV: IV With (RA) C (OR4), wherein R4 is (C? -C4) alkyl, for a time and under conditions sufficient to provide a compound of Formula III. A suitable amount of (RA) C (OR4) can be about 1 equivalent or more (against the compound of Formula IV). The processes of the first ring closure can be carried out in the presence or absence of a catalytic acid or base. The reaction is typically carried out in an organic solvent. Some suitable solvents include acetonitrile, or tetrahydrofuran. In the absence of the acid or base, temperatures suitable for carrying out the reaction of the first ring closure typically rise (eg, greater than room temperature, such as greater than about 25 ° C). The example of high temperatures may range from about 30 to about 100 ° C, or 50 to about 100 ° C, or about 75 to about 100 ° C. An acid may be suitable to catalyze the reaction of the first ring closure. Examples of acids include p-toluenesulfonic acid (pTSA), methanesulfonic acid, sulfuric acid, and acetic acid. In some embodiments, pTSA is used as an acid catalyst. Suitable temperatures for carrying out the acid catalyzed reaction can range from about 40 to about 100, about 40 to about 70, or about 40 to about 60 ° C. According to some embodiments, the reaction of the first ring closure is carried out in a mixture of l-methyl-2-pyrrolidinone and pTSA. In other embodiments, the reaction can be carried out in acetonitrile. In further embodiments, the reagent (RA) C (OR4) can be triethyl orthoacetate (where both RA and R4 are methyl) or triethyl orthoacetate. The present invention further provides processes for a second ring closure wherein a compound of Formula IV is prepared by (d) upon contacting a compound of Formula V: v with base for a time and under conditions sufficient to provide the compound of Formula IV. The base can be provided in any suitable amount, such as one equivalent or less (against the compound of Formula V). Any base may be suitable for carrying out the above processes for a reaction of the second ring closure. Examples of the preferred bases include hydroxides, amines, 1,5-diazabicyclo [4.3.0] -non-5-ene and imidazole. Less preferred examples include alkoxide. In some embodiments, the base is 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). The reaction of the second ring closure can be carried out in an organic solvent. Organic solvents include acetonitrile, l-methyl-2-pyrrolidinone, tetrahydrofuran, aqueous isopropyl alcohol or mixtures thereof. In some embodiments, the solvent includes l-methyl-2-pyrrolidinone or acetonitrile. Suitable temperatures for carrying out the reactions of the second ring closure may include lower temperatures, such as temperature under room temperature (eg, under 25 ° C), as well as temperatures in the ranges from about 0 to about 30 °. C. The example of temperatures can be in the range from about -20 to about 20, about -10 to about 10, about 0 to about 10, about 10 to about 20, about 20 to about 30, or around 30 to about 35 ° C. The ambient pressure is also adequate. The present invention further provides processes wherein a compound of Formula V is prepared by (e) by contacting a compound of Formula VI: VI wherein Y is an alkali metal or 2, wherein Z1 is halo and Z2 is alkaline earth metal, with semicarbazide, or acid addition salt thereof, for a time and under conditions sufficient to provide the compound of Formula VI. In some embodiments, semicarbazide is provided as semicarbazide hydrochloride. The semicarbazide can be provided in an amount greater than about 1 equivalent (against the compound of Formula VI or VII). According to some embodiments of the above semicarbazone forming processes, Y is an alkali metal such as K. In other embodiments, Y is Z1Z2 such as, for example, MgBr. In additional embodiments, the above semicarbazone forming processes are carried out at a pH of from about 1 to about 6, and more preferably from about 3 to about 5. Accordingly, by contacting the step ( e) can be carried out in the presence of an acid such as acetic acid, hydrochloric acid, sulfuric acid, propionic acid, or butyric acid. In some embodiments, the acid is acetic acid.

Still in further embodiments, the above semicarbazone forming processes can be carried out in an aqueous solvent. Additionally, the aqueous solvent may include alcohol such as, for example, isopropyl alcohol, methyl alcohol, ethyl alcohol, propyl alcohol, butyl alcohol, isobutyl alcohol, t-butyl alcohol, ethylene glycol or propylene glycol. In some embodiments, the aqueous solvent contains isopropyl alcohol.

Suitable reaction conditions for the above semicarbazone forming processes include room temperature and pressure. The example of temperatures can be in the range from around 20 to around 40 ° C. The present invention further provides aryl addition processes wherein a compound of Formula VI is prepared by (f) by contacting a compound of the Formula VII.

Ar VII With an addition reagent that has the formula: wherein: each RB and Rc is, independently, alkyl (C? ~ C4); in the presence of (t-BuO) Y for a time and under conditions sufficient to provide the compound of Formula VI. In some embodiments, Y is an alkali metal such as K. In other embodiments, Y is Z1Z2 such as, for example, MgBr. In some embodiments, the reagent (t-BuO) Y may be in excess of the addition reagent. For example, an appropriate amount of (t-BuO) Y may be about 1 to about 2 equivalents relative to the amount of the compound of the Formula VII. According to some embodiments, the addition reagent can be ethyl acetate (for example, RB is methyl and Rc is ethyl). The above aryl addition processes can be carried out at ambient or elevated temperatures, such as temperatures above 25 ° C. The example of elevated temperatures may be in the range from about 25 to about 60 or about 30 to about 50 ° C. The pressure to the environment is adequate. The present invention further provides compounds of Formula II or III: p m wherein: Ar is 2-methyl-4-methoxyphenyl, 2-chloro-5-fluoro-4-methoxyphenyl, or 2-methyl-6-methoxypyrid-3-yl; X is Cl; and each RA and RB is methyl. The present invention further provides compounds of Formula IV, V, or VI: He has IV V VI where: Y is an alkali metal or Z1Z2, where: Z1 is halo; and Z2 is an alkaline earth metal; Ar is phenyl or pyridyl substituted with 0 to 5 R3; Each R3 is independently H, halo, CN, nitro, (C? -C4) alkyl, (C? -C4) alkoxy, (C1-C4) haloalkyl, or haloalkoxy (C _. C4); and each RA and RB is methyl. In some embodiments, the compounds of Formulas IV, V, and VI are substituted where Ar is 2-methyl-4-methoxyphenyl, 2-chloro-5-fluoro-4-methoxyphenyl, or 2-methyl-6-methoxypyridyl. 3-ilo. In further embodiments, compounds of Formula VI are provided where Y is K. Reaction Scheme I provides an example of a process for preparing pyrazolo [1,5-a] -1,3,5-triazines according to the present invention.

Reaction scheme I II POX3 stage 5 amine rv m vp The present invention further provides methods for preparing aryl or heteroaryl acetonitrile derivatives (eg, the compounds of Formula VII) as intermediates in the processes for preparing the CRF antagonist of the compounds of Formula I. Accordingly, the present invention covers processes for preparing compounds of Formula VIII: wherein each A1, A2, A3, A4 and A5 is, independently, F, Cl, Br, alkyl (C? -C4), haloalkyl (C1-C4), alkoxy (C? C4), or haloalkoxy; comprising: (a) contacting a compound of Formula IX: With cyanide in the presence of an acid for a time and under conditions sufficient to provide the compound of Formula VIII. In some embodiments, A1 is Cl, A2 is H, A3 is methoxy, A4 is F, and A5 is H. According to some embodiments of the processes for preparing compounds of Formula VIII, by contacting the stage (a ) can be carried out in the presence of an ammonium salt. The example of benzyltrialkylammonium salts include salts such as benzyltributylammonium chloride, or tetraalkylammonium salts. The ammonium salt can be provided in an amount of about less than 1 eq, or less than 0.1 eq (against the compound of Formula IX). In further embodiments of the processes for preparing compounds of Formula VIII, the cyanide in contacting step (a) may be provided as a cyanide salt such as sodium or potassium cyanide. Acetone cyanohydrin can also be used. The cyanide may be provided in an amount of about 1 equivalent or greater (against the compound of Formula IX). In some embodiments, about 3 to 4 equivalents of cyanide are provided. Still in further embodiments of the processes for preparing compounds of Formula VIII, prior to contacting step (a), the compound of Formula IX can be dissolved in an organic solvent and the cyanide and the ammonium salt can be dissolved in a solvent aqueous. In this way, the contact can be carried out such that individual reagents are dissolved in non-miscible (or weakly miscible) solvents, creating a two-phase reaction system. Any combination of non-miscible solvents may be suitable, provided the reagents are sufficiently soluble. An example of a combination of a non-miscible solvent that can form a two-phase system is the combination of organic solvent and water. The example of organic solvents that are not miscible in water include, pentane, hexanes, benzene, toluene, diethyl ether, or mixtures thereof. The combination of nonmiscible solvent in the presence of an ammonium salt catalyst forms the basis of phase transfer catalysis (PTC). PTC will be understood by those skilled in the art to have a significant increase in the ratio of compound formation such as compound of Formula VIII. In some embodiments, the two-phase system includes toluene and water. For example, the compound of Formula IX can be dissolved in toluene and the cyanide and ammonium salt can be dissolved in water. Still in further embodiments of the processes for preparing compounds of Formula VIII, the acid upon contacting step (a) may be a weak carboxylic acid, such as propionic, butyric, or isobutyric acid. A preferred exemplary acid is acetic acid. The acid may be provided in an amount of about less than one equivalent (against the compound of Formula IX). An exemplary amount is around 0.3 to about 0.4 eq.

The above processes for preparing compounds of Formula VIII can be carried out at ambient or elevated temperatures, such as temperatures above 25 ° C. Examples of elevated temperatures may be in the range from about 25 to about 40 or about 30 to about 40 ° C. The environmental pressure is adequate. According to some embodiments, the compounds of Formula IX can be prepared b (b) by contacting a compound of Formula X: X with HBr for a time and under conditions sufficient to provide the compound of Formula IX. An adequate amount of HBr may be greater than one equivalent (relative to the compound of Formula X) greater than 10 equivalents, or between about 10 and 20 equivalents. By contacting step (b) which involves compounds of Formula X and HBr can be carried out at any suitable temperature and pressure. The initial contact can be carried out at low temperatures, such as from about 0 to about 20 C or about 0 to about 15 C and then then rising to higher temperatures such as from about 25 to about 60 ° C. or around 30 ° C to around 55 ° C. The ambient pressure is adequate. The compound of Formula X can be dissolved in any suitable solvent system. Exemplary solvents include organic solvents, such as those that are not miscible in water. In further embodiments, the compound of Formula X can be prepared by (c) contacting a compound of Formula XI: XI with reducing agent for a time and under conditions sufficient to provide the compound of Formula X.

Any suitable reducing agent can be used. The amount of reducing agent can be about one or more reducing equivalents. Exemplary reducing agents include bis (2-methoxyethoxy) aluminum hydride (Red-Al), lithium aluminum hydride, lithium borohydride, aluminum borohydride, borane, aluminum hydride, triethyl lithium borohydride, sodium borohydride with ligands of appropriate activation and certain enzymes. In some embodiments, the reducing agent is aluminum bis (2-methoxyethoxy) hydride and sodium (Red-Al).

Suitable solvent systems for contacting step (c) in the preparation of compounds of Formula X, can be, for example, organic solvents that are inert to strong reducing agents. Exemplary solvents include benzene, toluene, diethyl ether, tetrahydrofuran, pentane, hexanes, mixtures thereof, and the like. In some embodiments, a suitable solvent is toluene. By contacting step (c), it involves compounds of Formula XI, it can be carried out at any suitable temperature. Some of the adequate temperatures fall below 25 C, including temperatures in the range from about 0 to about 20, about 10 to about 20, or about 14 to about 17 ° C. The environmental pressure is adequate. The present invention also provides compounds of Formula VIII, IX, or X: wherein A1 is Cl, A2 is H, A3 is methoxy, A4 is F, and A5 is H. An exemplary process of preparing compounds of Formula VIII is provided below in Reaction Scheme II.

Reaction Scheme II The present invention also provides processes for preparing compounds of Formula XI: vrp comprising (a) contacting a compound of the Formula XII: with methoxide for a time and under conditions sufficient to provide the compound of Formula XI. The methoxide can be provided in a greater amount than about 2 eq. (Against the compound of Formula XII). An exemplary amount of methoxide is about 3 eq. Suitable solvent systems include methanol. The temperature and environmental pressure is also adequate. In some embodiments, compounds of Formula XII can be prepared by (b) contacting a compound of Formula XIII: with oxalyl chloride or thionyl chloride for a time and under conditions sufficient to provide the compound of Formula XII. Oxalyl chloride or thionyl chloride may be provided in an amount of at least about one equivalent (against the compound of Formula XIII). An exemplary amount of oxalyl chloride or thionyl chloride is about 2 eq. In some embodiments, contacting step (b) in the preparation of compounds of Formula XII is carried out in the presence of DMF. DMF can be provided in an amount that is less than one equivalent (eq) (against the compound of Formula XIII). Exemplary amounts of DMF include between about 0.3 and about 0.6 eq. Additionally, by contacting step (b) in the preparation of compounds of Formula XII can be carried out in the presence of an organic solvent, such as (DMF), toluene, or mixtures thereof, or any other solvent that does not react with the reagents. Suitable temperatures for preparing compounds of Formula XII can be less than about 25 ° C. In some embodiments, the initial temperature at which contacting stage (b) is carried out is lower than 25 ° C, and which then rises to above 25 ° C at a later point in time , such as at a temperature from about 40 to about 60 ° C. The excess oxalyl chloride can be removed by distillation according to known procedures. The present invention further provides a compound of Formula XI: XI.

Processes for preparing compounds of Formula XI are illustrated in Reaction Scheme III.

Reaction Scheme III The present invention further provides processes for preparing compounds of Formula XIV: xrv wherein each B1, B2, B3, and B4 is, independently, F, Cl, Br, alkyl (C? -C4), haloalkyl (C? -C4), alkoxy (C? ~ C4), or haloalkoxy (C1-) C4). In some embodiments, B1 is H, B2 is H, B3 is methoxy, and B4 is methyl. The processes for preparing compounds of Formula XIV comprise contacting a compound of Formula XV: XV with cyanide for a time and under sufficient conditions to provide the compound of the Formula XIV. Any source of cyanide is adequate. In some embodiments, cyanide is provided as sodium cyanide. The cyanide reagent can also be delivered in an amount that is about one or more equivalents relative to the compound of Formula XV. In some embodiments, about 3 to about 4 equivalents of cyanide are supplied. By contacting step (a) to prepare compounds of Formula XIV may optionally be carried out in the presence of an iodide salt. Any iodide salt is suitable, including for example, sodium or potassium salts. The iodide can be provided in a catalytic amount, such as less than one equivalent relative to the compound of Formula XV. In some embodiments, about 0.1 eq of iodide is supplied. In the preparation of compounds of Formula XIV, contacting step (a) can be carried out at any suitable temperature or pressure. In some embodiments, the contact is carried out at room temperature and pressure. In some embodiments, Formula XV can be prepared by (b) contacting a compound of Formula XVI: XVI with a chlorinating agent for a time and under conditions sufficient to provide the compound of Formula XV. Any chlorinating agent is adequate. In some embodiments, the chlorinating agent is mesyl chloride or thionyl chloride. The mesyl chloride may be provided in an amount of at least about one equivalent relative to the compound of Formula XVI. The thionyl chloride may be provided in an amount of at least about 0.5 equivalents relative to the compound of Formula XVI. In the preparation of compounds of Formula XV, by contacting step (b) can be carried out in any suitable solvent. In some embodiments, the solvent includes acetonitrile. Any temperature or pressure may be appropriate. In some embodiments, the contacting is carried out at a temperature or from about 0 to about 10 ° C or about 0 to about 5 ° C. According to some embodiments, the compounds of Formula XVI are prepared by contacting a compound of Formula XVII: xvp with a reducing agent for a time and under conditions sufficient to provide the compound of Formula XVI.

Any sufficient reducing agent is suitable, and may be provided in an amount of at least about one equivalent relative to the compound of Formula XVII. In some embodiments, the reducing agent is NaBH 4. NaBH 4 can be provided in an aqueous hydroxide solution (for example, about 10 to about 20 M NaOH). By contacting step (c) to prepare compounds of Formula XVI, suitable solvents include those that are inert to the reducing agent. In some embodiments, the solvent includes alcohol, such as methanol, ethanol, isopropanol, etc. , and mixtures thereof. According to some embodiments, compounds of Formula XVII can be prepared by (d) contacting a compound of Formula XVIII: XVIII with n-BuLi followed by a formylation reagent for a time and under conditions sufficient to provide the compound of Formula XVII. The n-BuLi may be provided in an amount of about 1 eq relative to the compound of Formula XVII. Compounds of Formula XVII can also be prepared by contacting a compound of Formula XVIII with a reagent capable of a metal-halogen exchange, such as magnesium, lithium, or alkyl lithium. Suitable formylation reagents include (DMF), ethyl formate, N-formylpiperidine, N-methoxy-N-ethylformamide. According to some embodiments, the formylation reagent is DMF. The formylation reagent can be provided in an amount of at least about one equivalent (relative to the compound of Formula XVIII). In some embodiments, the formylation reagent is supplied in an amount of about two eq. Suitable solvents to contact the stage (d) in the preparation of compounds of Formula XVII are inert to n-BuLi such as, for example, benzene, toluene, hexanes, pentane, and the like. Tetrahydrofuran may also be adequate. Suitable temperatures can be in the range from -80 to about 0 ° C, such as around -60 ° C, for initial contact. Ambient temperature and pressure are adequate after initial contact. An exemplary process for the preparation of the compounds of Formula XIV is provided in Reaction Scheme IV.

Reaction Scheme IV XIV XV stage 3 t chlorine xvp XVI xvm The present invention further provides processes for preparing compounds of Formula XIX: XIX wherein: B4 is F, Cl, Br, alkyl (C? -C), haloalkyl (C1-C4), alkoxy (Ca-C4), or haloalkoxy (Cj-C); and B5 is alkyl (C? -C4); comprising: contacting a compound of Formula XX: AA with B50"for a time and under conditions sufficient to provide the compound of Formula XIX According to some embodiments, B5 may be methyl or B4 may be methyl In additional embodiments B50 ~ is provided as an alkaline salt such as a Sodium or potassium salt Reagent B50 ~ can be provided in excess, such as for example more than 1 eq relative to the amount of compound of Formula XX When contacting step (a) can be carried out in any Suitable solvents Some suitable solvents include methanol, benzene, toluene, and the like The temperatures suitable for the acuals the contact of step (a) can be carried out include temperatures between about 0 and 120 ° C. For example, the temperature it can be from around 60 up to around 80 ° C or around 65 up to around 75 ° C. Environmental pressure is adequate.

In further embodiments, the compound of Formula XX can be prepared by (b) contacting a compound of Formula XXI: XXI or acid addition salt thereof, with nitrite and Br2 in the presence of acid for a time and under conditions sufficient to provide the compound of Formula XX. In some modalities, the nitrite can be provided as NaN02 or HONO. In additional embodiments, the acid can be HBr. Each of the nitrite, Br2, and the acid can be provided in excess, such as, for example, more than 1 eq relative to the amount of compound of Formula XXI. By contacting step (b) can be carried out at any suitable temperature. Example temperatures may range from about -10 to about 20, about -5 to about 10, or about 0 to about 5 ° C. The reaction mixture resulting from contacting step (b) may also be contacted with base to adjust the pH to a value greater than about 7. For example, hydroxide (such as NaOH or KOH, etc.). ) can be added to achieve a pH in solution of about 8 to about 14, about 10 to about 14, or about 13. In some embodiments, the compound of Formula XXI can be prepared by (c) contacting a compound of Formula XXII: xxp with Br2 in the presence of acid for a time and under conditions sufficient to provide the compound of Formula XXI. In some embodiments, the acid is acetic acid. By contacting step (c) it can be carried out at any suitable temperature and pressure. Some of the right temperatures can be from around 10 to around 25, around 15 to around 20 or around 18 ° C. The acid may be provided in excess relative to the compound of Formula XXII and may serve as a solvent. Bromine (Br2) can be provided in an amount of about 0.5 to about 1.5, about 0.9 to about 1.1 or about 1.0 eq relative to the compound of Formula XXII. The present invention further provides compounds of Formula XIV or XV: wherein B1 is H, B2 is H, B3 is methoxy, and B4 is methyl.

An exemplary process for the preparation of the compounds of Formula XIX is given in Reaction Scheme V. Reaction Scheme V XXII stage 1 XXI The process described herein can be monitored in accordance with any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as magnetic resonance spectroscopy (e.g., 1H or 13C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography. The term "contacting" as used herein refers to bringing the set of reagents with sufficient distances to effect molecular transformations such as breakage and bond formation. The reagents provided for contacting can be in any form such as gas, liquid, solid or solution. The reactions of the processes described herein can be carried out in suitable solvents, such as organic or aqueous solvents, which can be easily selected by one skilled in the art of organic synthesis. Suitable solvents may not be substantially reactive with the starting materials (reagents), intermediates or products at the temperatures at which the reactions are carried out, that is, temperatures which may be in the range of the freezing temperature of the solvent at the boiling temperature of the solvent. A given reaction can be carried out in a solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected. Suitable organic solvents may include halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachlorethylene, trichlorethylene, 1,1-trichloroethane, 1,2- trichloroethane, 1,1-dichloroethane, 2-chloropropane, hexaf luorobenzene, 1, 2, 4-di chlorobenzene, o-dichlorobenzene, chlorobenzene, f luorobenzene, fluorotri chloromethane, chlorotrif luoromethane, bromine trif luoromethane, tetraf carbon luoride, dichlorof luoromethane, chlorodif luoromethane, chlorodifluoromethane, trifluoromethane, 1. 2-dichlorotetraf luoroethane, hexafluoroethane, 1-chlorobutane and 1,2-dichloroethane. Suitable organic solvents include ethers such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, dimethyl ethylene glycol ether, diethyl ethylene glycol ether, diethylene glycol dimethyl ether, diethyl ether diethylene glycol, dimethyl triethylene glycol ether, anisole, t-butyl methyl ether, di-n-butyl ether, or 1,3-dioxolane. Suitable protic solvents may include, for example, and without limitation, water or organic solvents such as methanol, ethanol, 2-nitroethanol, 2-f luoroethanol, 2, 2, 2-trifluoroethanol., ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo alcohol -pentyl, t-pentyl alcohol, diethylene glycol monomethyl ester, monoethyl diethylene glycol ether, cyclohexanol, benzyl alcohol, phenol, glycerol, or l-methoxy-2-propanol. Suitable aprotic solvents may include, by way of example and without limitation, the organic solvents tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3, 4, 5, 6-tetrahydro- 2 (1H) -pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylphormamide, acetonitrile, dimethyl sulfoxide, propionitrile, formate ethyl, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N, N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, hexamethylphosphoramide, n-propyl acetate, isopropyl acetate, n-butyl acetate , ethyl propionate, 2-pentanone, or methyl iso-butyl ketone. Suitable organic solvents include hydrocarbons such as benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene. As used herein, suitable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and organic acids. Suitable organic acids include formic acid, acetic acid, propionic acid, butanoic acid, methanesulfonic acid, p-toluene sulfonic acid, benzenesulfonic acid, trifluoroacetic acid, propiolic acid, butyric acid, 2-butinoic acid, vinyl acetic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid and decanoic acid. As used herein, suitable bases include, but are not limited to: lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, magnesium hydroxide, calcium hydroxide, calcium carbonate, sodium bicarbonate and potassium bicarbonate. As used herein, suitable strong bases include, but are not limited to, alkoxides, metal amides, metal hydrides, metal dialkylamides and arylamines, wherein; the alkoxides include lithium, sodium and potassium salts of methyl, ethyl and t-butyl oxides; metal amides include sodium amide, potassium amide and lithium amide; Metal hydrides include sodium hydride, potassium hydride and lithium hydride; and metal dialkylamides include sodium and potassium salts of methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, trimethylsilyl and substituted cydohexyl amides. The compounds described herein may have asymmetric centers. Unless indicated otherwise, all chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, C = N double bonds, and the like can also be present in the compounds described herein, and all stable isomers are contemplated in the present invention. It will be appreciated that the compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic forms or by synthesis. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended. The present invention includes all isotopes of the atoms presented in the intermediates or final compounds. Isotopes include those atoms that have the same atomic number but different mass numbers. For example, hydrogen isotopes include tritium and deuterium. When any variable occurs more than once in any constituent or in any formula, its definition every presented is independent of its definition every third presence. Thus, for example, if a group is shown to be substituted with 0-3 Rz, then the group can optionally be replaced with up to three different Rz. The term "substituted" as used herein, means that any one or more hydrogen in the designated atom is replaced with a selection of the indicated group, with the proviso that the normal valence of the designated atom is not exceeded and that the results in the substitution are a stable compound. The term "alkyl" as used herein means that it refers to a saturated hydrocarbon group which is straight chain, branched or cyclized ("cycloalkyl"). The alkyl groups can be substituted or unsubstituted with one or more of these hydrogens, replaced by another chemical group. The example of the alkyl groups include methyl (Me), ethyl (Et), propyl (for example, n-propyl and isopropyl), butyl (for example, n-butyl, isobutyl, t-butyl), pentyl (for example, n-pentyl, isopentyl, neopentyl), cyclopentyl, cyclohexyl, norbornyl, and the like. "Alkenyl" refers to alkyl groups having one or more double carbon-carbon bonds. The example of the alkenyl groups include ethenyl, propenyl, cyclohexenyl, and the like. "Alkynyl" refers to alkyl groups having one or more triple carbon-carbon bonds. The example of alkynyl groups includes ethynyl, propynyl, and the like. "Haloalkyl" refers to straight, branched chains and alkyl cyclyl groups having one or more halogen substituents. Haloalkyl groups include CF3, C2Fs, CC13, CHC12, C2C15 and the like. The term "alkoxy" refers to an -O-alkyl group. The example of the alkoxy groups includes methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. "Haloalkoxy" refers to an alkoxy group substituted by one or more halogens. The term "cycloalkyl" refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems. The example of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so on. "Halo" or "halogen" include fluoro, chloro, bromo, and iodo. The "aryl" groups refer to monocyclic or polycyclic aromatic hydrocarbons, including for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. Aryl portions are well known and are described, for example in Hawley 's Condensed Chemical Dictionary (13 ed.), R. J. Lewis, ed., J. Wiley &; Sons, Inc., New York (1997), which is incorporated herein by reference in its entirety. Aryl groups can be substituted or unsubstituted. The "Heteroaryl" groups are monocyclic and polycyclic aromatic hydrocarbons that include at least one ring member of heteroatoms such as sulfur, oxygen or nitrogen. Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1, 2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, benzoxazolin-2-on-yl, indolinyl, benzodioxolanyl, benzodioxane, and the like. Heteroaryl groups can be substituted or unsubstituted. The "heterocyclyl" groups can be saturated (that is, they can not contain double or triple bonds) or unsaturated (that is, they can contain one or more double or triple bonds) the carbocyclyl groups wherein one or more of the carbon atoms formed in the ring of the carbocyclyl group is replaced by a heteroatom such as O, S or N. The heterocyclyl groups can be substituted or unsubstituted. Examples of heterocyclyl groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranoyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, and the like. Some examples of heterocyclyl substituents may include C?-C5 alkyl, C3-C6 cycloalkyl, C2-Cd alkenyl, C2-Cg alkynyl, halogen, C?-C4 haloalkyl, CN, OR7, SH, N02, 0CF3, S (0) nR7, COR7, C02R7, OC (0) R7, NR7C0R8, N (COR7) 2, NR7CONR7R8, NR7C02R8, NR7R8, or CONR7R8, wherein R7 and R8 are as defined above according to the first aspect of the invention. The heterocyclyl groups can be substituted with any number of substituents, such as, for example, 0 to 7.0 to 6.0 to 5.0 to 0.4 to 3.0 to 2, or 0 to 1 substituents. The compounds prepared by the methods described herein can be used to treat disorders characterized by abnormal levels of corticotropin releasing factor (CRF) in mammals. Some disorders characterized by abnormal levels of corticotropin releasing factor include mood disorders such as depression, including major depression, simple episode depression, recurrent depression, depression induced by abuse in children, seasonal affective depression, postpartum depression, dystemia, bipolar disorders and cyclothymia; anxiety disorders that include panic, phobias, obsessive-compulsive disorder, traumatic stress disorder, and tension-induced sleep disorders; inflammation, pain, chronic fatigue syndrome; tension induced headache; Cancer; infections by the human immunodeficiency virus (HIV), neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn's disease, spastic colon, diarrhea and ileus postoperatively, and hypersensitivity associated with disturbances or psychopathological stress; eating disorders such as anorexia and bulimia nervosa; supranuclear palsy; Amyotrophic Lateral Sclerosis; immune suppression; hemorrhagic tension, psychotic episodes induced by tension; euthyroid disease syndrome; inadequate antidiarrheal hormone syndrome (ADH); obesity; sterility; traumas in the head; trauma of the spine; ischemic neuronal damage (for example, cerebral ischemia such as cerebral ischemia of the hippocampus); excitotoxic neuronal damage; epilepsy; cardiovascular disorders including hypertension, tachycardia and congestive heart failure; apoplexy; immune dysfunctions including stress-induced immune dysfunctions (eg, stress-induced fevers, porcine stress syndrome, bovine embarkation fever, paroxysmal fibrillation and confinement-induced dysfunctions in chickens, stress by deviation in sheep or stress related to the interaction of humans and animals in dogs); muscle spasms; urinary incontinence; senile dementia of the Alzheimer's type; dementia due to multiple infarctions; Amyotrophic Lateral Sclerosis; dependencies and chemical addictions (for example, dependencies on alcohol, cocaine, heroin, benzodiazepines or other drugs); symptoms due to the withdrawal of alcohol and drugs; osteoporosis, psychosocial dwarfism; hypoglycemia; hair loss; abnormal circadian rhythm; and disorders related to abnormal circadian rhythm such as syndrome of change of time zone; seasonal cash disorder; irregular pattern of sleep and awakening, delayed sleep phase syndrome, advanced sleep phase syndrome, sleep arousal disorder that is not 24 hours, light-induced clock readjustment, REM sleep disorders, hypersomnia, parasomnia, narcolepsy, nocturnal enuresis, tired legs syndrome, sleep apnea, dysthymia and abnormal circadian rhythm associated with chronic administration and withdrawal of antidepressant agents. Thus, the compounds provided herein, due to their antagonism of CRF receptors, are expected to be useful in the treatment of these and other disorders. The compounds prepared by the processes of the present invention can be administered to treat the above disorders by any suitable means that allow the compound to come into contact with the site of action of the compound, such as a CRF receptor, in the body of a mammal. The compounds can be administered by any of the conventional means available by use in conjunction with pharmaceuticals either as an individual therapeutic agent or in combination with other therapeutic agents. The compounds can be administered alone, or in combination with a pharmaceutical carrier on the basis of the route chosen for administration and standard pharmaceutical practice. The dose of the compound is administered several times depending on various factors such as the pharmacodynamic character of the particular compound, and its mode and route of administration, the age of the recipient, weight and health; nature and degree of symptoms; type of concurrent treatment; frequency of treatment; and desired effect. For use in the treatment of the disorders or conditions above, the compounds of this invention can be orally administered daily at a dose of the active ingredient (eg, a compound of formula I) of about 0. 002 to about 200 mg / kg of body weight. For example, a dose of around 0. 01 to about 10 mg / kg can be divided into small doses and administered one up to four times a day. Alternatively, sustained release formulations may be effective in obtaining the desired pharmacological effect. Dosage forms (compositions) suitable for administration may contain from about 1 mg to about 100 mg of active ingredient per unit dose. In these pharmaceutical compositions, the active ingredient (eg, a compound of formula I) may be present in an amount of about 0. 5 to 95% by weight based on the total weight of the composition.

The active ingredient (e.g., a compound of the formula I) can be administered orally in solid dosage forms such as capsules, tablets and powders, or in liquid forms such as elixirs, syrups and / or suspensions. The compounds can also be administered parenterally in sterile liquid dose formulations. The gelatin capsules can be used to contain the active ingredient and a suitable carrier such as, but not limited to, lactose, starch, magnesium stearate, spherical acid or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide continuous release of the drug over a period of time. The compressed tablets may be sugar coated or film coated to hide any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract. Liquid dosage formulations for oral administration may also contain coloring or flavoring agents to increase patient acceptance. Typically, water, pharmaceutically acceptable oils, saline solutions, aqueous dextrose, and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration may contain, for example, a water soluble salt of the active ingredient and suitable stabilizing agents. Antioxidant agents, such as sodium bisulfide, sodium sulfite or ascorbic acid, either alone or in combination, can act as stabilizing agents. Also suitable as stabilizing agents are citric acid and its salts, and EDTA. In addition, parenteral solutions may contain preservatives such as, for example, benzalkonium chloride, methyl or propyl paraben and chlorobutanol. The compounds prepared by the processes described herein can also be used as reagents or standards in the biochemical study of neurological function, dysfunction and disease. As those skilled in the art will appreciate, numerous changes and modifications may be made to the preferred embodiments of the invention without departing from the spirit of the invention. It is intended that all variations fall within the scope of the invention. Through this specification, various groupings are used to conveniently write variable constituents of the compounds and groups of several related portions. It is specifically intended that each presentation of such groups through this specification include every possible sub-combination of the members of the groups, including the individual members of the mimes. It will be intended that each of the patents, applications and printed publications mentioned in this patent document be incorporated by reference thereinto in their entirety. EXAMPLES Example 1: Preparation of potassium salt of 2- (4-methoxy-2-methylphenyl) -3-oxobutyronitrile Under anhydrous conditions, (4-methoxy-2-methylphenyl) acetonitrile (25.0 kg, 155 moles, commercially available) and 68.3 kg of ethyl acetate were mixed to obtain a solution. The resulting solution was heated to 35 ° C and potassium t-butoxide in THF (100 kg, 20% by weight, 178 moles) was added over a period of 30 to 60 minutes by controlling the temperature at 35 ° C. Following the addition, the reaction mass was heated to 45 ° C and maintained for 60 minutes. At the end of the waiting period, the sample was analyzed by CLAR. The reaction mixture was then cooled to 25 ° C and combined with 3 other batches for a total of 843 kg of solution.

Example 2: Preparation of semicarbazone from 2- (4-methoxy-2-ethylphenyl) -3-oxobutyronitrile.

Four batches of the solution prepared according to Example 1 and water (150 kg) were combined. The solvent (557 kg) was distilled from the mixture at 145 mm Hg and 35 ° C. then, water (1200 kg), acetic acid (47.0 kg), semicarbazide hydrochloride (89.0 kg, 798 moles) and IPA (475 kg) were added. The resulting mixture was heated to 25-35 ° C and maintained for 21 hours. The reaction was monitored by CLAR. The semicarbazone form of 2- (4-methoxy-2-methylphenyl) -3-oxobutyronitrile was isolated by filtration and the cake washed with water (2 x 250 kg). A l of 143 kg was isolated. The purity was 99.3% by weight. The yield was 93.1% teoretical. Example 3: Preparation of 5-amino-4- (4-methoxy-2-methylphenyl) -3-methylpyrazole-1-carboxylic acid amide The semicarbazone of 2- (4-methoxy-2-methylphenyl) -3-oxobutyronitrile (160 g, 615 mmol) from Example 2 and N-methylpyrrolidinone (NMP, 480 L) was charged and the resulting thick paste was cooled to < 5 ° C. 1.8-Diazabicyclo [5.4.0] undec-7-ene (DBU, 18.0 mL, 120 mmol) was added. The reaction mass was maintained at < 5 ° C for 1.0 to 1.5 hours. The conversion to the amide of 5-amino-4- (4-methoxy-2-methylphenyl) -3-methylpyrazole-1-carboxylic acid was monitored by HPLC (typically greater than 95%). Example 4: Preparation of 8- (4-methoxy-2-methylphenyl) -2,7-dimethylpyrazolo [1, 5-a] [1,3,5] triazin-4-ol.

P-Toluenesulfonic acid (29.2 g, 154 mmol) in acetonitrile (100 L) was added to the reaction mixture described in Example 3 containing the acid amide. The resulting mixture was heated to 85-90 ° C and trimethyl orthoacetate (160 L, 1.26 mol) was added for 5 minutes hard heating. The reaction is maintained for about 45 minutes in the desired range with a total of 1.5 hours of heating time from the initiation of the heating cycle. The progress of the reaction was monitored by CLAR. Water (1.50 L) was added for 5 minutes with one drop at a temperature up to about 60 ° C. The resulting mixture was cooled to about 20 ° C for 1 hour and the product was isolated by filtration. The yield was 136 g (78.0% with a purity of 99.5 A%). Example 5: Preparation of N, N-bis (2-ethoxyethyl) -8- (4-methoxy-2-methyl-phenyl) -, 7- dimethylpyrazolo [1,5-a] [1,3,5] benzenesulfonate riazin-4-amine.

The 8- (4-methoxy-2-methylphenyl) -2,7-dimethylpyrazolo [1, 5-a] [1,3,5] triazin-4-ol from Example 4 (6.50 kg, 22.5 mol), benzyltributylammonium (4.70 kg, 15.0 mol), acetonitrile (6.50 L) and methyl t-butyl ether (26.0 L) was charged and the resulting thick paste was treated with phosphorus oxychloride (3.30 L, 34.9 mol) and N, N- diisopropylethyl amine (6.00 L, 34.3 mol). The resulting mixture was heated to 50-55 ° C and maintained for about 1.5 hr at which time the reaction was complete. The resulting solution was cooled to about 0 ° C and treated with bis (2-methoxyethyl) amine (8.50 L, 57.5 mol) while maintaining the batch temperature < 25 ° C. The lot is maintained for about 1. 0 hour and then treated with a solution of potassium hydroxide (11.4 kg, 203 mol) in water (78.0 L) and maintained for 3-4 hr. The phases were divided and the organic portion washed with water (32.5 L). Additional methyl t-butyl ether (163 L) was added and the batch was filtered to remove the particular material. The batch was distilled under reduced pressure to remove the water and methyl t-butyl ether to a final point of about 47.0 L. The solution was cooled to about 0 ° C and filtered to remove the particular material. The salt was prepared by first adding acetonitrile (6.11 L) to the batch followed by the portionwise addition of an acid solution (3.58 kg, 22.6 mol) in methyl t-butyl ether (6.50 L) with seeding. The resulting thick paste was allowed to form for about 2.0 hours prior to cooling to about 0 ° C, where the batch is maintained for about 30 minutes, before being isolated by filtration. Drying provided 10.7 kg (83.8% of the theory). Example 6: Preparation of 2-chloro-5-fluoro-4-methoxy-benzoic acid methyl ester A solution of 2-chloro-4,5-difluoro-benzoic acid (15.0 kg, 99% by weight of purity, 77.1 moles, 1.00 eq) and dimethylformamide (0.2 kg, 2.73 moles, 0.04 eq) in toluene (75.9 kg) was treated with oxalyl chloride (19.8 kg, 156.0 moles, 2.02 eq) while maintaining the temperature at < 25 ° C for 2 hours. The mixture was heated to 50 ° C and held for 1 hour. At this point, CLAR indicated that the reaction was complete. The remaining oxalyl chloride was removed by distillation, the temperature of the vessel rises from 85 to 110 ° C reflecting the removal of boiling oxalyl chloride until the toluene was only distilled. The cold reaction mass was transferred to another vessel containing 25% by weight of sodium methoxide in methanol (50.5 kg.233.7 moles, 3.03 eq) in methanol (90.0) The mixture was stirred overnight at 25 ° C and monitored by HPLC.The methanol was removed by distillation at 50 ° C / 150 mmHg in vacuo while the volume was maintained by the addition of toluene (total of 184.6 kg was added) The distillation was continued until the methanol content by GC was 1.16 v / v% The resulting solution was washed sequentially (each of the first stirring for 15 minutes) with water (150.0 kg), 1.6% by weight of hydrochloric acid (37.0 kg), aqueous sodium bicarbonate (1.85 kg of sodium bicarbonate in 33.15 kg of water), and water (35.0 kg) .The washed solution was filtered through a 0.2 micron cartridge filter and the volume halved by distillation at 50 ° C / 150 mmHg under vacuum The mixture was heated to 80 ° C to re-dissolve the solids that appear and heptane was added (68.0 kg) ) while the temperature was maintained at 70 ° C. The thickened mixture was cooled to 5 ° C and remained The crystals were collected by filtration, washed with heptane (34.0 kg) and dried at 50 ° C / 50 mmHg to provide 14.4 kg (85% yield) of the methyl ester product of 2-chloro acid. -5-fluoro-4-methoxy-benzoic acid. Example 7: Conversion of methyl ester of 2-chloro-5-f luoro-4-methoxy-benzoic acid to (2-chloro-5-f luoro-4-methoxy-phenyl) -acetonitrile A solution of methyl 2-chloro-5-fluoro-4-methoxybenzoate (2.00 kg of 99.04% by weight of material, 9.06 moles, Example 6) in toluene (17.0 L) was cooled to 13-15 ° C, treated with a 65% by weight solution of Red-Al aluminum hydride (sodium bis (2-methoxyethoxy), 2.95 L, 9.83 moles, 1.08 eq) for 1 hour while maintaining the temperature at 13-17 ° C. The sample by CLAR at this point states that all the starting material is reacted. The remaining Red-Al was quenched by the addition of acetone (40 mL). The reaction mass was transferred to a 48% hydrobromic acid solution (19.0 L, 168 moles, 18.5 eq) previously cooled to 8 ° C. The addition took 40 minutes at < 50 ° C. The reaction mixture was heated to 50 ° C and held for 30 minutes at which point HPLC indicated 999: 1 of 1-bromoethyl-2-chloro-5-fluoro-4-methoxybenzene to (2-chloro-5-fluoro- 4-methoxyphenyl) methanol. The phases were separated and the organic phase was washed successively with water 5 times (2.0 L) until the pH of the aqueous wash was extended to 5. The solution was filtered through a cartridge filter to produce 18.1 kg of solution, I analyze as 13.17% by weight l-bromomethyl-2-chloro-5-fluoro-4-methoxybenzene. This intermediate was mixed with acetic acid (195 mL, 3.4 moles, 0.36 eq.). A solution of sodium cyanide (1780 g, 36.3 moles, 3.84 eq) and benzyltributyl ammonium chloride (195 g, 0.63 moles, 0.07 eq) in water (7.85 L) was added for 1 minute with vigorous stirring. This mixture was washed with additional water (2.0 L) and the temperature was adjusted to 35 ° C. It was stirred continuously during 2. 5 hours and the CLAR was sampled to indicate a relationship of (2-Chloro-5-fluoro-4-methoxy-phenyl) -acetonitrile to 1-bromomethyl-2-chloro-5-fluoro-4-methoxybenzene from 1999: 1. The phases were separated and the organic phase was washed with water (18.5 L). This lot was combined with another batch prepared on the same scale. The solution was concentrated by rotary evaporation at < 50 ° C until the level was ~ 12 L, at which point the concentration was continued but the level was maintained by the addition of isopropanol. This concentration procedure is continued until GC indicated that the toluene content was 2.09% v / v. A total of 18 L of isopropanol were required. The volume was diluted to 16.5 L with IPA and the solids were dissolved by heating. The solution was cooled to 45 ° C and the pressure reduced to 120 mmHg to distill isopropanol while water was added to maintain volume. The temperature was maintained at 45-50 ° C. A total of ~ 15 L of water was loaded for 5 hours before the GC analysis indicated that the level of isopropanol was reduced to 5.7%. The thick mixture was cooled to room temperature overnight and the crystals were collected by filtration. The cake was washed with water (5 L) for several washes and the crystals were dried under vacuum at (25"-635 mm vacuum) for 4 days to provide 3.533 kg of 99.17% by weight purity (97% correct yield) ) of (2-chloro-5-fluoro-4-methoxy-phenyl) -acetonitrile Example 8: Preparation of HBr salt of 5-bromo-2-amino-6-picoline 2-am? No-6-p? Col? Na salt HBr of 5-bromo-2-am? No-6-p? Col? Na impurity of dibromo Variation 1 The 2-Amino-6-picoline (39.8 kg, 99.6% by weight purity, 367 mol, 1.00 eq) was charged in acetic acid (65.0 kg) while the temperature was raised to 60 ° C. Additional acetic acid (17 kg) was charged to wash in the last of the picolines and the mixture was heated to 35 ° C until the solution occurred. After cooling to 18 ° C, bromide (56.2 kg, 352 mol, 0.96 eq) was charged 18 ± 3 ° C for 2 hours. More acetic acid (2.0 kg) was charged to wash in the last of the bromides. The mixture was kept at this temperature range for 1 hour and then cooled to 11-15 ° C. This stayed in this range for 0. 5 hours . The solids were coated by filtration in polypropylene and washed with isopropanol (63.0 kg) to yield 69.6 kg of wet 5-bromo-2-amino-6-pi choline hydrobromide (76% by weight of product as bromohydrate). This corresponds to a 54% yield. Part of this product was dried for the purposes of recording the 13 C NMR spectrum: 13 C NMR (400 MHz, DMSO-de) d 154.1, 146.9, 112.4, 105.2, 20.1. Variation 2 The 2-Amino-6-picoline (16.0 kg, 99.6% by weight purity, 147 mol, 1.00 eq) was charged in acetic acid (35.0 kg) while the temperature was maintained at <50 ° C. Additional acetic acid (2 kg) was charged to wash in the last of the picoline and the mixture was heated to 35 ° C until the solution occurred. After cooling to 18 ° C, bromide (23.0 kg, 144 mol, 0.98 eq) was charged at 18 ± 3 ° C for 2 hours. More acetic acid (2.0 kg) was charged to wash in the last of the bromides. The mixture was kept at this temperature range for 1 hour and water was charged (41 L). The pH was adjusted to 4. 0 with 30% sodium hydroxide and the solids were collected in a polypropylene bag in a spin (the additional recovery of the product from these solids is described below) and the pH was adjusted to 13. 3 with 30% aqueous sodium hydroxide (75 kg). The solids were collected in a polypropylene bag in a spin and washed with water (50 L). The solids were combined by drying with those recovered as described below. The additional product was recovered by recovering the solids that were precipitated in the filtrate of the first filtration described above. These solids were dissolved in water (30 L) and the pH was adjusted to 13.5 with 50% aqueous sodium hydroxide (20.0 kg). The solids were filtered in a polypropylene bag in a spin and the solids were washed with water (30 L). These were combined with HBr salt of 5-bromo-2-amino-6-pi-choline isolated above to be dried. Meanwhile, the impurity of the dibromo cake that was collected by the first filtration was stirred in water (100 L) and filtered in a polypropylene bag in a spin and the solids were washed with water (30 L). The filtrate / wash was recharged to the reactor and the pH was adjusted to 12 5 with 50% aqueous sodium hydroxide (12.5 L) and more water (150 L). The solids were filtered in a polypropylene bag in a spin and the solids were washed with water (60 L). These were combined with the HBr salt solids of 5-bromo-2-amino-6-picoline previously isolated and all were dried together at 40 ° C for 3 days to provide 16.2 kg of the solids (95.6% in that). ) or 56% yield. Example 9: Conversion of the HBr salt of 5-bromo-2-amino-6-picoline to 2, 5-dibromo-6-picoline HBr salt of 5-bromo-2-amino-B-picoline 2,5-dibromo-6-picoline Variation 1 5-Bromo-2-amino-6-picoline hydrobromide (29.4 kg, 76.5% by weight purity, 84 mol, 1.00 eq) was dissolved in 48% hydrobromic acid (162.0 kg, 961 mol, 11.44 eq ) a > 35 ° C. The solution was cooled to 2 ° C and the bromine was charged (43.0 kg, 269 mol, 3.20 for 40 min.) A solution of 40% by weight of sodium nitrite (28.9 kg, 419 mol, 4.99 eq) was charged for 50 minutes. minutes at -1 to 5 ° C. The contents were kept for 1 hour and the pH was adjusted to 13.1 using 50% aqueous sodium hydroxide (120.0 kg) The contents were heated at 20 ° C for 1 hour and charged with toluene (78.0 kg) The mixture was stirred for 30 minutes and allowed to settle overnight.The organic phase was clarified by filtration and washed twice with a saturated aqueous sodium chloride solution (51.1 kg). kg of a 2,5-dibromo-6-picoline solution (17.3% by weight) or 79% yield.

Variation 2 5-Bromo-2-amino-6-picoline (7.0 kg) and 5-bromo-2-amino-6-picoline bromohydrate (7.0 kg) (the base in the analysis of starting material, equals 11 kg or 41 mol of the starting material) were dissolved in 48% hydrobromic acid (107.0 kg, 635 mol, 15.49 eq) at < 35 ° C. The solution was cooled to 2 ° C and bromide (27.3 kg, 171 mol, 4. eq) was charged for 45 minutes at 0-5 ° C. A solution of sodium nitrite (8.1 kg, 117 mol, 2.86 eq) in 20 L of water was charged for 1.5 hours at -1 to 5 ° C. The contents were maintained for 1 hour and the pH was adjusted to 12.5 using 50% aqueous sodium hydroxide (70.0 kg). The contents heated up 20 ° C for 1 hour and the solids were collected in a polypropylene bag in a spin. The solids were washed with water (75 L) to produce 12.0 kg of wet 2, 5-dibromo-6-picoline, determining 83% by weight of the product (68% yield). Part of this was dried for the purposes of recording the 1 H NMR spectrum: 13 C NMR (400 MHz, CDC 13) d 158.8, 141.9, 139.4, 126.7, 120.6, 24.7. Example 10: Conversion of 2,5-dibromo-6-picoline to 2-methoxy-5-bromo-6-picoline to 2-methoxy-5-bromo-6-picoline. 2,5-dibromo-6-picoline 2-methoxy-5-bromo-6-picoline A solution of 2,5-dibromo-6-picoline (30.6 kg, 122 mol, 1.00 eq) in toluene (154.2 kg) was dried by vacuum distillation at 40 ° C / 75 mmHg to remove 105.7 kg of the distillate to produce a solution containing 40 ppm of water. This was mixed with 25% by weight of sodium methoxide in methanol (124.1 kg, 574 mol, 4.71 eq) and the mixture was heated to 65-75 for 6 hours until the reaction was complete (the CLAR analysis indicates 1.6% of the area of the remaining starting material). The mixture was cooled to 5 ° C and water (98 L) was charged to the mixture followed by t-butyl methyl ether (97 kg). The layers were separated and the organic phase was washed twice with 5% brine (139 kg) and once with 20% brine (165 kg). The organic phase was clarified by filtration and 51 kg were recovered by vacuum distillation at 40 ° C to produce a solution of 2-methoxy-5-bromo-6-picoline (58.4 kg) of 40.6% by weight purity (96%) of performance). Part of this was purified by distillation for purposes of recording the 13 C NMR spectrum: 13 C NMR (400 MHz, CDC 13) d 162.4, 154.4, 142.0, 111.8, 109.5, 53.6, 24.6. Example 11: Conversion of 2-methoxy-5-bromo-6-picoline to benzyl aldehyde derivative.

A solution of 2-methoxy-5-bromo-6-picoline (73% by weight of the solution in toluene, 3.17 kg, 11.45 moles) in THF (18.3 L) was cooled to -60 ° C and treated with 2.5 N butyl lithium in hexanes (4.87 L, 12.2 mol, 1.06 eq). After 0.5 h, dimethylformamide was charged (1.76 L, 22.8 mol, 2.0 eq). After 0.5 h, ammonium chloride (1.6 kg / 16.2 L water) was charged and the layers separated. The aqueous phase was re-extracted with methyl t-butyl ether (3.3 L) and the combined organic extracts were washed with saturated brine (2.5 L). This was a total of 22.4 kg of organic solution (7.08% by weight) which corresponds to 92% yield of the solution. Example 12: Conversion of the aldehyde derivative to the alcohol derivative The solution of the benzyl aldehyde was prepared as above in example 11, solvent was removed under vacuum to methanol at 25-35 ° C. This was repeated until the water analysis was < 0.1%. The final solution indicated less than 7.7% of the benzyl aldehyde. This solution was cooled to 0 ° C and 12% by weight of the sodium borohydride solution (12% by weight in 14 M aqueous sodium hydroxide, 660 mL, 2.9 moles, 1.10 eq) was added to 0-5. ° C. The volatile components were evaporated to < 35 ° C, methyl t-butyl ether (3 L) and continuous evaporation were added. The residue was diluted with methyl t-butyl ether (4.8 L) and water (3.9 L), and the layers were separated. The aqueous phase was further extracted with methyl t-butyl ether (0.8 L). The combined organic layer consists of 6,238 kg (25.16% by weight AJ2153) or a 97.6% yield of the solution was based on the analysis after solvent exchange. Example 13: Conversion of the alcohol derivative to the chloride derivative The solution prepared above in example 12, was exchanged with solvent by acetonitrile until the water content was < 400 ppm. The solution was diluted with acetonitrile (8.6 L) and cooled to 0-2 ° C. Thionyl chloride (0.78 kg, 6.6 mol, 0.64 eq) was added at 0-5 ° C. More of the volatile components were evaporated at 25-35 ° C and the residue was dissolved in methyl t-butyl ether (4.7 L) and saturated sodium bicarbonate solution (4.7 L). Solid sodium bicarbonate (1.41 kg) was added to complete the neutralization.

The phases were separated, more water (12 L) was added to the aqueous phase and this was also extracted with methyl t-butyl ether (2.4 L). The combined organic layers were washed with saturated brine (0.5 L). The organic solution weighed 7.8 kg (16.42% by weight), corresponding to 72.9% yield of the solution. Example 14: Conversion of the chloride derivative to the nitrile derivative About half the volume of the solution prepared above as described in Example 13 was completely distilled and the remaining diluent with isopropanol (7.4 L). A solution of sodium cyanide (1.79 kg, 36.6 moles, 4.9 eq) and sodium iodide (0.11 kg, 0.73 moles, 0.1 in water (4.6 L) was charged in. The reaction was stirred until LC indicated a chloride ratio. benzyl / benzyl cyanide from 1/100 @ 220 nm The layers were allowed to settle and the aqueous layer was re-extracted with ethyl acetate (4.2 L) The combined organic solutions were concentrated at 35-40 ° C to brown solids This was dissolved in water (1.5 L) and ethyl acetate (8.2 L) and the layers were separated The aqueous layer was re-extracted with ethyl acetate (2.6 L) and the combined organic layers were washed with a mixture of water. 1: 1 saturated brine plus water (1.3 L) The organic solution was dried with magnesium sulfate (0.26 kg), filtered, and concentrated to 25-35 ° C. The fully distilled volume was replaced with ethyl acetate until the water content was <400 ppm The weight of the organic solution was 2.68 kg (41.3% by weight) This corresponds to 91.4% of the performance of the solution. Example 15: Biological assay The compounds prepared by the processes of the present invention can have CRF receptor antagonist activity. A compound can be considered active if it has a value of less than about 10,000 nM for the inhibition of CRF. The Ki values can be determined by any suitable biological assay, such as, for example, the assay described below. An example of a CRFi receptor binding assay, which can be used for the evaluation of the biological activity of the compounds of the present invention, is provided herein. The example also includes the isolation of cell membranes containing human CRFi receptors cloned for use in the binding assay. The messenger RNA is isolated from the human hippocampus by standard techniques. The RNA is reverse transcribed using the oligo (dt) 12-18 and the coding region is amplified by PCR from the start and stop codons. The fragment obtained by PCR fragment was cloned into the EcoRV site of pGEMV, where the insert was recovered using Xhol + Xbal and cloned in the Xhol + Xbal sites of the pm3ar vector (which contains a promoter of CMV promoter, the SV40"t" junction and the early poly A signals, an origin of viral replication of Epstein-Barr, and a selection marker for hygromycin). The resulting expression vector, designated phchCRFR, is transfected into 293EBNA cells, and the cells that retain the episome in the presence of 400 μM hygromycin are selected. Cells that survive 4 weeks of hygromycin selection accumulate, adapt for growth in suspension and are used to generate the memebranas for the binding assay described below. Individual aliquots containing approximately 1 x 108 suspended cells are then centrifuged to pelletize and freeze. For the binding assay, the frozen pellet described above containing 293EBNA cells transfected with receptors, is homogenized in 10 mL of ice-cold tissue buffer (50 mM HEPES buffer, pH 7.0, containing 10 mM MgCl 2). mM EGTA, 1 μg / 1 aprotinin, 1 μg / 1 leupeptin and 1 μg / ml pepstatin). The homogenate is centrifuged at 40,000 x g for 12 min and the resulting pelletized again in 10 mL of tissue buffer. After further centrifugation at 40,000 x g for 12 min, the pellet is resuspended to a protein concentration of 360 μg / ml for use in the assay.

The binding assays are carried out in 96-well plates; each well has a capacity of 300 μl. To each well is added 50 μl of dilutions of the test drug (final concentration of the drugs in the range from 10 ~ 10 to 10 ~ 5 M). lOOμl of 125I-ovine-CRF (125I-o-CRF) (final concentration 150 pM) and 150μl of the homgeneized cell described above. The plates were then allowed to incubate at room temperature for 2 hours before filtering the incubation on GF / F filters (pre-set with 0.3% polyethylenimine) using a suitable cell harvester. The filters are rinsed 2 times with ice-cold assay buffer before removing the individual filters and evaluating them by radioactivity in a gamma counter. The inhibition curves of the binding of 125 I-o-CRF to cell membranes at various dilutions of the test drug are analyzed by the iterative curve fitting program LIGAND Munson, et al. , Anal. Biochem. , 1980, 107, 220, which is incorporated herein by reference in its entirety, which provides Ki values for inhibition which are then used to evaluate biological activity. Other in vitro assays for the determination of the activity of the CRFi receptor antagonist of the present compounds are described, for example, in Endocrinology, 1985, 116, 1653 and in Peptides, 1985, 10, 179, each of which is it is incorporated herein by reference in its entirety. The binding activity of the receptor of the compounds can also be evaluated according to the methods described in Grigoriadis, et al., Biochemical, Pharmacological, and Autoradiographic Methods to Study Corticotropin-Releasing Factor Receptors. Methods in Neurosciences, Vol. 5,1991, which is incorporated herein by reference in its entirety. Example 16: Inhibition of the Activity of Cyclase Adenylate Stimulated by CRF. The activity of the present compounds can be studied by the inhibition of the activity of adenylate cyclase stimulated by CRF, which can be carried out as described by Battaglia, et al., Synapse, 1987, I, 572, which is incorporated herein by reference in its entirety. The tests are carried out at 37 ° C for 10 min in 200 mL of buffer containing 100 mM Tris-Cl (pH 7.4 at 37 ° C), 10 mM MgCl2, 0.4 mM EGTA, 0.1% BSA, mM isobutylmethylxanthine (IBMX), 250 units / ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5'-triphosphate, 100 nM oCRF, antagonist peptides (concentration range 10 ~ 9 to 10 ~ 6 M) and 0.8 mg of tissue with original wet weight (approximately 40-60 mg of protein). The reactions were initiated by the addition of 1 mM ATP / 32PJATP (approximately 2-4 mCi / tube) and finalized by the addition of 100 mL of 50 mM Tris-HCL, 45 mM ATP and 2% sodium dodecyl sulfate. In order to observe the recovery of cAMP, lμl of [3H] cAMP (approximately 40,000 dpm) is added to each tube prior to separation. The separation of [32 P] cAMP from [32 P] ATP is effected by sequential elution on Dowex and alumina columns. Example 17: Biological assay In vivo The in vivo activity of the compounds of the present invention can be evaluated by using any of the biological assays available and accepted within the art. Examples of in vivo biological assays for testing the anxiolytic activity of the compounds include the "drinking test with punishment" (Vogel, et al., Psychopharmacologia, 1971, 21, 1, which is incorporated herein by reference. In its whole); "higher elevation maze test" (Pellow, et al., J. Neurosci. Methods, 1985, 14, 149, which is incorporated herein by reference in its entirety); "stress-induced cortical norepinephrine release" (Funk, et al., Brain Res., 1996, 741, 220, which is incorporated herein by reference in its entirety); "proof of light and darkness" (Misslin, et al., Behav. Process, 1989, 8, 119, which is incorporated herein by reference in its entirety); "Four plate test" (Boissier, et al., Eur. J. Pharmacol., 1968, 4, 145, which is incorporated herein by reference in its entirety); and the "battery of mouse defense tests" (Griebel, et al., Aggress. Behav., 1997, 23, 19, which is incorporated herein by reference in its entirety). The compounds can be tested on any species of rodent or small mammal. Examples of in vivo biological assays for the anti-depressant-like activity test of the compounds include the "forced swimming test" (Porsolt, et al., Nature, 1977, 266, 730, which is incorporated herein by reference). reference in its entirety) and the "CMS test" (Willner, et al., Clin. Neuropharmacol., 1992, 15 (item 1), 550A, which is incorporated herein by reference in its entirety). Other useful models for testing compounds for their anxiolytic or antidepressant activity are detailed in Berridge, et al., Brain Research Reviews, 1990, 15, 71, which is incorporated herein by reference in its entirety. Models for testing the activity of the compounds for other indications are well known in the art. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

Claims: Having described the invention as above, the content of the following claims is claimed as property. 1. A process for preparing a compound of the formula characterized in that: Ar is phenyl or pyridyl substituted with 0 to 5 R3; each R1 and R2 is, independently, H, (C? -C8) alkyl, or alkoxyalkyl (Ci-Ce); each R3 is, independently, H, halo, CN, nitro, alkyl (C? -C), (C1-C4) alkoxy, haloalkyl (C? ~ C4), or haloalkoxy (C1-C4); and each RA and RB is, independently, (C1-C4) alkyl; comprising: (a) contacting a compound of Formula III: IH with POX3 in the presence of an amine, selected from diisopropylethylamine, diethylphenylamine, diisopropylaniline, diethylaniline, diisopropylisobutylamine, tribencylane, triphenylamine, trichlorohexylamine, or diethylisopropylamine wherein X is halo, for a time and under conditions sufficient to provide a compound of the Formula II: Y; ?? (b) contacting the compound of Formula II with NHR-'R2 for a time and under conditions sufficient to provide the compound of Formula I. 2. The process according to claim 1, characterized in that X is Cl. 3. The process according to claim 1, characterized in that the amine is diisopropylethylamine. 4. The process according to claim 1, characterized in that NHR1R2 is 5. The process according to claim 1, characterized in that RA is methyl. 6. The process according to claim 1, characterized in that RB is methyl. The process according to claim 1, characterized in that the contacting of step (b) can be carried out in the presence of an ammonium salt. 8. The process according to claim 7, characterized in that the ammonium salt is benzyltriethyl ammonium chloride, benzyltributyl ammonium chloride, or methyltrialkyl (C8-C? 0) ammonium chloride. 9. The process according to claim 7, characterized in that the ammonium salt is benzyltributylammonium chloride. 10. The process according to claim 1, characterized in that the contacting of step (b) is carried out in the presence of organic solvent. 11. The process according to claim 10, characterized in that the organic solvent comprises one or more of methyl t-butyl ether, acetonitrile, isopropyl acetate, toluene or 1-chlorobutane. 12. The process according to claim 10, characterized in that the organic solvent is a mixture of acetonitrile and methyl t-butyl ether. The process according to claim 1, characterized in that the contacting of step (a) was carried out at a temperature of about 50 to about 70 ° C. 14. The process according to claim 1, characterized in that the compound of formula II is not isolated prior to contacting step (b). 15. The process according to claim 1, characterized in that: Ar is 2-methyl-4-methoxyphenyl; R1 is methoxyethyl; R2 is methoxyethyl; RA is methyl; and RB is methyl. 16. The process according to claim 1, characterized in that: Ar is 2-chloro-5-fluoro-4-methoxyphenyl; R1 is H; R2 is pent-3-yl; RA is methyl; and RB is methyl. 17. The process according to claim 1, characterized in that: Ar is 2-methyl-6-methoxypyrid-3-yl; R1 is H; R2 is but-2-yl; RA is methyl; and RB is methyl. 18. The process according to claim 1, characterized in that the compound of the formula III is prepared by (c) contacting a compound of the formula IV: With (RA) C (OR4), wherein R4 is (Cx-C4) alkyl, for a time and under conditions sufficient to provide a compound of Formula III. 19. The process according to claim 18, characterized in that R4 is methyl. 20. The process according to claim 18, characterized in that RA is methyl. 21. The process according to claim 18, characterized in that RB is methyl. 22. The process according to claim 18, characterized in that the contacting of step (c) was carried out in the presence of acid or base. 23. The process according to claim 22, characterized in that the contacting of step (c) was carried out in the presence of acid. 24. The process according to claim 23, characterized in that the acid is p-toluenesulfonic acid. 25. The process according to claim 18, characterized in that the contacting of step (c) was carried out in the presence of organic solvent. 26. The process according to claim 25, characterized in that the organic solvent comprises 1-methyl-2-pyrrolidinone. 27. The process according to claim 18, characterized in that the contacting of step (c) was carried out at a temperature of about 40 to about 100 ° C. 28. The process according to claim 18, characterized in that the compound of the formula IV is prepared by (d) contacting a compound of the formula V: V with base for a time and under conditions sufficient to provide the compound of Formula IV. 29. The process according to claim 28, characterized in that the base is 1,8-diazabicyclo [5.4.0] undec-7-ene (DBÜ). 30. The process according to claim 28, characterized in that the contacting of step (d) was carried out in an organic solvent. 31. The process according to claim 30, characterized in that the organic solvent comprises 1-methyl-2-pyrrolidinone. 32. The process according to claim 28, characterized in that the contacting of step (d) was carried out at a temperature of about 0 to about 30 ° C. 33. The process according to claim 28, characterized in that the compound of the formula V is prepared by (e) contacting a compound of the formula VI: wherein Y is an alkali metal or Z Z, wherein Z 1 is halo and Z 2 is alkaline earth metal, with semicarbazide, or acid addition salt thereof, for a time and under conditions sufficient to provide the compound of the Formula VI. 34. The process according to claim 33, characterized in that Y is K. 35. The process according to claim 33, characterized in that the contacting of step (e) was carried out at a pH from about 3 to about 5. 36. The process according to claim 4, characterized in that the contacting of step (e) was carried out in the presence of acid. 37. The process according to claim 36, characterized in that the acid is acetic acid. 38. The process according to claim 33, characterized in that the contacting of step (e) was carried out in an aqueous solvent. 39. The process according to claim 38, characterized in that the aqueous solvent comprises alcohol. 40. The process according to claim 39, characterized in that the alcohol is isopropyl alcohol. 41. The process according to claim 33, characterized in that the contacting of step (e) was carried out at a temperature of about 20 to about 40 ° C. 42. The process according to claim 33, characterized in that the compound of the formula VI is prepared by (f) contacting a compound of the formula VII: NC- ^ Ar VII with an addition reagent having the formula: OR R B; A. O.R1 wherein: each RB and Rc is, independently, alkyl (C_-C4); in the presence of (t-BuO) Y for a time and under conditions sufficient to provide the compound of Formula VII. 43. The process according to claim 42, characterized in that Y is K. 44. The process according to claim 42, characterized in that the contacting of the step (f) was carried out at around 30 up to about 50 ° C. 45. A process for preparing a compound of formula II: p characterized in that: Ar is phenyl or pyridyl substituted with 0 to 5 R3; X is selected R3 is independently H, halo, CN, nitro, (C1-C4) alkyl, alkoxy (Ca-C4), haloalkyl (C1-C4) or haloalkoxy (C? -C); and each RA and RB is independently alkyl (C? -C4); which comprises contacting a compound of the formula III: ip with POX3 in the presence of an amine, selected from diisopropylethylamine, diethylphenylamine, diisopropylaniline, diethylaniline, diisopropylisobutylamine, tribencylamine, triphenylamine, tricyclohexylamine or diethylisopropylamine for a time and under conditions sufficient to provide a compound of Formula II. 46. The process according to claim 45, characterized in that X is Cl. 47. The process according to claim 45, characterized in that the amine is diisopropylethylamine. 48. The process according to claim 45, characterized in that the contacting was carried out in the presence of ammonium salt. 49. The process according to claim 48, characterized in that the ammonium salt is benzyltriethylammonium chloride, benzyltributylammonium chloride, or methyltrialkyl (C8-C? 0) ammonium chloride. 50. The process according to claim 48, characterized in that the ammonium salt is benzyltributylammonium chloride. 51. The process according to claim 45, characterized in that the contacting was carried out in an organic solvent. 52. The process according to claim 51, characterized in that the organic solvent comprises one or more methyl t-butyl ether, acetonitrile, isopropyl acetate, toluene or 1-chlorobutane. 53. The process according to claim 51, characterized in that the organic solvent is a mixture of acetonitrile and methyl t-butyl ether. 54. The process according to claim 45, characterized in that the contacting was carried out at a temperature of about 50 to about 70 ° C. 55. The process according to claim 45, characterized in that Ar is 2-methyl-4-methoxyphenyl, 2-chloro-5-fluoro-4-methoxyphenyl, or 2-methyl-6-methoxypyrid-3-yl. 56. A process for preparing a compound of formula III: characterized in that: Ar is phenyl or pyridyl substituted with 0 to 5 R3; each R3 is independently H, halo, CN, nitro, alkyl (L-C4), alkoxy (_-C4), haloalkyl (C? -C) or haloalkoxy (C? -C4); and each RA and RB is independently (C1-C4) alkyl; which comprises contacting a compound of formula IV: with (RA) C (OR 4), wherein R 4 is (C 1 -C 4) alkyl, for a time and under conditions sufficient to provide a compound of Formula III. 57. The process according to claim 56, characterized in that R4 is methyl. 58. The process according to claim 56, characterized in that RA is methyl. 59. The process according to claim 56, characterized in that RB is methyl. 60. The process according to claim 56, characterized in that the contacting was carried out in the presence of an acid or base. 61. The process according to claim 60, characterized in that the contacting was carried out in the presence of an acid. 62. The process according to claim 61, characterized in that the acid is p-toluenesulfonic acid. 63. The process according to claim 56, characterized in that the contacting was carried out in the presence of an organic solvent. 64. The process according to claim 63, characterized in that the organic solvent comprises 1-methyl-2-pyrrolidinone. 65. The process according to claim 56, characterized in that the contacting was carried out at a temperature of about 40 to about 100 ° C. 66. A process for preparing a compound of the formula IV characterized in that? R is phenyl or pyridyl substituted with 0 to 5 R3; each R3 is independently H, halo, CN, nitro, (C? -C4) alkyl, (C1-C4) alkoxy, haloalkyl (C? -C4) or haloalkoxy (C? ~ C); and RB is alkyl (C? -C4); which comprises contacting a compound of formula V: V wherein RB is (C? -C4) alkyl with 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) for a time and under conditions sufficient to provide the compound of Formula IV. 67. The process according to claim 66, characterized in that the contacting was carried out in an organic solvent. 68. The process according to claim 67, characterized in that the organic solvent comprises 1-methyl-2-pyrrolidinone. 69. The process according to claim 66, characterized in that the contacting was carried out at a temperature of about 0 to about 30 ° C. 70. A process for preparing a compound of formula V: characterized in that: V Ar is phenyl or pyridyl substituted with 0 to 5 R3; each R3 is independently H, halo, CN, nitro, alkyl (C? -C4), alkoxy (C? -C4), haloalkyl (C1-C4) or haloalkoxy (C1-C4); and RB is (C1-C4) alkyl; which comprises contacting a compound of formula VI: VI where Y is an alkali metal or Z1Z2, where Z1 is halo and Z2 is alkaline earth metal, with semicarbazide, or acid addition salt thereof, for a time and under conditions sufficient to provide the compound of Formula VI. 71. The process according to claim 70, characterized in that Y is K. 72. The process according to claim 70, characterized in that RB is methyl. 73. The process according to claim 70, characterized in that the contacting was carried out at a pH from about 3 to about 5. 74. The process according to claim 70, characterized in that the contacting It was carried out in the presence of an acid. 75. The process according to claim 74, characterized in that the acid is acetic acid. 76. The process according to claim 70, characterized in that the contacting was carried out in an aqueous solvent. 77. The process according to claim 76, characterized in that the aqueous solvent comprises alcohol. 78. The process according to claim 77, characterized in that the alcohol is isopropyl alcohol. 79. The process according to claim 70, characterized in that the contacting was carried out at a temperature of about 20 to about 40 ° C. 80. A process for preparing a compound of formula VI: SAW characterized because: Y is K; Ar is phenyl or pyridyl substituted with 0 to 5 R3; each R3 is independently H, halo, CN, nitro, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl or (C1-C4) haloalkoxy; and RB is alkyl (C_-C4); which comprises contacting a compound of formula VII: VII with an addition reagent having the formula: wherein: each RB and Rc is, independently, (C1-C4) alkyl; in the presence of (t-BuO) Y for a time and under conditions sufficient to provide the compound of Formula VI. 81. The process according to claim 80, characterized in that the addition reagent is ethyl acetate. 82. The process according to claim 80, characterized in that the contacting was carried out at about 30 to about 50 ° C. 83. A compound of formula II or formula III: II m characterized in that: Ar is 2-methyl-4-methoxyphenyl, 2-chloro-5-fluoro-4-methoxyphenyl, or 2-methyl-6-methoxypyrid-3-yl. X is Cl; and each RA and RB is methyl. 84. A compound of the formula IV, V or VI: IV V VI characterized in that: Y is an alkali metal or Z1Z2, wherein: Z1 is halo; and Z2 is an alkaline earth metal; Ar is phenyl or pyridyl substituted with 0 to 5 R3; each R3 is independently H, halo, CN, nitro, (C? -C4) alkyl, (C1-C4) alkoxy, haloalkyl (C? -C4), or haloalkoxy (C1-C4); and each RA and RB is methyl. 85. The process according to claim 84, characterized in that Ar is 2-methyl-4-methoxyphenyl, 2-chloro-5-fluoro-4-methoxyphenyl, or 2-methyl-6-methoxypyrid-3-yl. 86. The process according to claim 84, of formula VI, characterized in that Y is K. 87. A process for preparing a compound of formula VIII: vm wherein each A1, A2, A3, A4 and A5 is, independently, F, Cl, Br, (C_-C4) alkyl, haloalkyl (C_L-C4), alkoxy (Ca-C4), or haloalkoxy; characterized in that it comprises: (a) contacting a compound of formula IX: IX with cyanide in the presence of an acid for a time and under sufficient conditions to provide the compound of Formula VIII. 88 The process according to claim 87, characterized in that the contacting was carried out in the presence of an ammonium salt. 89 The process according to claim 88, characterized in that the ammonium salt is a benzyltrialkylammonium salt. 90 The process according to claim 88, characterized in that the ammonium salt is benzyltributylammonium chloride. 91 The process according to claim 87, characterized in that the cyanide is provided as sodium cyanide. 92 The process according to claim 87, characterized in that prior to contacting the compound of the formula IX, it was dissolved in an organic solvent and the cyanide and ammonium salt were dissolved in aqueous solvent. 93. The process according to claim 92, characterized in that the contacting was carried out in a two-phase system. 94. The process according to claim 87, characterized in that A1 is Cl, A2 is H, A3 is methoxy, A4 is F and A5 is H. 95. The process according to claim 87, characterized in that the acid is acidic. acetic. 96. The process according to claim 87, characterized in that the compound of the formula IX is prepared by (b) by contacting a compound of the formula X: X with HBr for a time and under conditions sufficient to provide the compound of Formula IX. 97. The process according to claim 96, characterized in that the compound of the formula X was prepared by (c) by contacting a compound of the formula XI: XI with reducing agent for a time and under conditions sufficient to provide the compound of Formula X. 98. The process according to claim 97, characterized in that the reducing agent is sodium bis (2-methoxyethoxy) aluminum hydride (Red -To the). 99. The process according to claim 97, characterized in that the contacting of step (c) was carried out in an organic solvent. 100. The process according to claim 99, characterized in that the organic solvent is toluene. 101. The process according to claim 97, characterized in that the contacting of step (c) was carried out at a temperature of about 10 to about 20 ° C. 102. A process for preparing a compound of the formula characterized in that it comprises (a) contacting a compound of formula XII: with methoxide for a time and low enough conditions to provide the compound of Formula XI. 103 The process according to claim 102, characterized in that the methoxide was dissolved in methanol. 104 The process according to claim 102, characterized in that the compound of the formula XII was prepared by (b) contacting a compound of the formula XIII: with chloride for a time and under conditions sufficient to provide the compound of Formula XII. 105. The process according to claim 104, characterized in that the contacting of step (b) was carried out in the presence of dimethylformamide (DMF). 106 The process in accordance with the claim 104, characterized in that the contacting of step (b) was carried out in the presence of toluene. 107 A compound of the formula VIII, IX or X: vip ix x characterized in that A1 is Cl, A2 is H, A3 is methoxy, A4 s F and A5 is H. 108. A compound of formula XI 109. A process for preparing a compound of formula XIV: XIV wherein each B1, B2, B3, and B4 is, independently, F, Cl, Br, (C 1 -C 4) alkyl, (C 1 -C 4) haloalkyl, (C 1 -C 4) alkoxy, or haloalkoxy (C 1 -C 4) ). characterized in that it comprises (a) contacting a compound of formula XV: XV with cyanide for a time and under conditions sufficient to provide the compound of Formula XIV. 110. The process in accordance with the claim 109, characterized in that the cyanide is provided as sodium cyanide. 111. The process in accordance with the claim 109, characterized in that the contacting was carried out in the presence of an iodide salt. 112. The process according to claim 109, characterized in that B1 is H, B2 is H, B3 is methoxy and B4 is methyl. 113. The process according to claim 109, characterized in that the compound of formula XV is prepared by (b) contacting a compound of formula XVI: XVI with a chlorinating agent for a time and under sufficient conditions to provide the compound of Formula XV. 114 The process according to claim 113, characterized in that the chlorinating agent is mesyl chloride (MsCl). 115 The process according to claim 113, characterized in that B1 is H, B2 is H, B3 is methoxy and B4 is methyl. 116. The process according to claim 113, characterized in that the co-compound of formula XVI was prepared by (c) contacting a compound of formula XVII: xvp with a reducing agent for a time and under conditions sufficient to provide the compound of Formula XVI. 117. The process according to claim 116, characterized in that the reducing agent is NaBH 4. 118. The process according to claim 116, characterized in that B1 is H, B2 is H, B3 is methoxy, and B4 is methyl. 119. The process according to claim 116, characterized in that the compound of formula XVII is prepared by (d) contacting a compound of formula XVIII: with n-BuLi followed by a formylation reagent for a time and under conditions sufficient to provide the compound of Formula XVII. 120. The process according to claim 116, characterized in that the formylation reagent is dimethylformamide (DMF). 121. The process according to claim 119, characterized in that B1 is H, B2 is H, B3 is methoxy, and B4 is methyl. 122. A process for preparing a compound of formula XIX:?.?. characterized in that: B4 is F, Cl, Br, alkyl (^ d), haloalkyl (C? -C4), (C1-C4) alkoxy, or haloalkoxy (C? -C4); and B5 is (C1-C4) alkyl; comprising: (a) contacting a compound of Formula XX: XX with B50 ~ for a time and under conditions sufficient to provide the compound of Formula XIX. 123. The process according to claim 122, characterized in that B5 is methyl. 124. The process according to claim 122, characterized in that B4 is methyl. 125. The process according to claim 122, characterized in that the compound of the formula XX was prepared by (b) contacting a compound of the formula XXI: XXI or acid addition salt thereof, with nitrite and Br2 in the presence of acid for a time and under sufficient conditions to provide the compound of Formula XX. 126 The process according to claim 125, characterized in that B4 is methyl. 127 The process according to claim 125, characterized in that the nitrite is provided as NaN02. 128 The process according to claim 125, characterized in that the acid is HBr. 129. The process according to claim 125, characterized in that the co-compound of formula XXI was prepared by (c) contacting a compound of formula XXII: xxp with Br2 in the presence of acid for a time and under conditions sufficient to provide the co-option of Formula XXI. 130 The process according to claim 129, characterized in that B4 is methyl. 131 The process according to claim 129, characterized in that the acid is acetic acid. 132. A process for preparing a compound of the formula XX where B4 is F, Cl, Br, alkyl (C? -C4), haloalkyl (C? -C4), (C? -C4) alkoxy, or haloalkoxy (C? -C4), characterized in that it comprises contacting a compound of the formula XXI or acid addition salt thereof, with nitrite and Br2 in the presence of acid for a time and under conditions sufficient to provide the compound of Formula XX. 133. The process according to claim 132, characterized in that B4 is methyl. 134. The process according to claim 132, characterized in that the nitrite is provided as NaN02. 135. The process according to claim 132, characterized in that the acid is HBr. 136. A process for preparing a compound of formula XXI: wherein B is F, Cl, Br, (C 1 -C 4) alkyl, haloalkyl (C 1 -C 4), alkoxy (C 1 -C 4), or haloalkoxy (Cy-Cj), characterized in that it comprises contacting a compound of the formula XXII: XXII with Br in the presence of acid for a time and under conditions sufficient to provide the compound of Formula XXI. 137 The process according to claim 136, characterized in that B4 is methyl. 138 The process according to claim 136, characterized in that the acid is acetic acid. 139 A compound of the formula XIV or XV: characterized in that B1 is H, B2 is H, B3 is methoxy, and B4 s is methyl.